Process for preparing n-aryl-alpha-oxocyclopolymethylene amines an related compounds

ABSTRACT

THE INVENTION IS DIRECTED TO N-ARYL-A-OXOCYCLOPOLYMETHYLENE AMINES AND N-ARYL-A-IMINOCYCLOPOLYMETHYLENE AMINES WHICH ARE CENTRAL NERVOUS SYSTEM DEPRESSANTS.

United States Patent O 3,637,746 PROCESS FOR PREPARING N-ARYL-a-OXOCYCLO- POLYMETHYLENE AMINES AND RELATED COMPOUNDS Peter H. L. Wei, Upper Darby, and Stanley C. Bell, Penn Valley, Pa., assignors to American Home Products Corporation, New York, NY. No Drawing. Filed June 10, 1968, Ser. No. 735,540 Int. Cl. C0711 27/ 08 US. Cl. 260-3265 1 Claim ABSTRACT OF THE DISCLOSURE The invention is directed to N-aryl-a-oxocyclopolymethylene amines and N-aryl-a-oxo-a'-iminocyclopolymethylene amines which are central nervous system depressants.

This invention relates to new and novel N-aryl-a-oxocyclopolymethylene amines and N-aryl-a-oxo-d-iminocyclopolymethylene amines and to a process for their preparation.

The compounds within the purview of the present invention are exemplified by those having the following formula:

Where R and R are hydrogen, halogen, lower alkyl, lower alkoxy or sulfamoyl;

R is halogen, lower alkyl, lower alkoxy; and

i n is an integer from 2 to about 4.

As used herein, the terms lower alkyl, lower alkoxy and the like describe groups containing from 1 to 8 carbon atoms.

When the compounds of this invention are depicted by structural Formula I they are generically designated as N-aryl-a oxocyclopolymethylene amines. A typical example of these compounds when n=2 is 1-(2,6-dichlorophenyl)-2-azetidinone; when n=3 is 1-(2-methoxy-4- chlorophenyl)-2-pyrrolidinone; and 'when n=4 is 1-(2,4- diethyl-G-sulfamoylphenyl) -2-piperidinone.

Alternatively, when the compounds of this invention are depicted by structural Formula II they are generically designated as "N-aryl-a-imino-a-oxocyclopolymethylene amines. A typical example of these compounds when n=2 is l-(2,6-dichlorophenyl)-5-iminopyrrolidin-2-one; when n=3 is 1-(2-methoxy 4 chlorophenyl)-6-iminopiperidin-2-one; and when it=4 is 1-(2,4-diethyl-6-sulfamoylphenyl)-7-iminohexahydroazepin-Z-one.

The new and novel compounds of this invention may be prepared by the process which is hereinafter schematically illustrated.

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R1 *NHZ acylation R2 XCO(OH2)11X R -NHCO(CH X cyclization 0 it} E 2) J R N Iminocyclizatlon 1 N 01: Bi a 2 R3 IQ H (I) (H) To prepare the N-aryl-a-oxocyclopolymethylene amines (I) and the N-aryl-u-oxo-a'-iminocyclopolymethylene amines (H) of the present invention, a two step procedure is utilized. In the first step a 2-substituted aniline (III) is contacted with a haloalkanoyl halide (IV) in an organic solvent, such as chloroform, at a temperature range from about 0 C. up to the reflux temperature for a period of about 1 to about 4 hours. When the reaction is complete, the resulting intermediate compound haloalkanoyl anilide (V) may be separated and recovered by well known means. For example, the reaction mixture is allowed to stand until separation of the product is complete. Thereafter, the solvent may be removed and the residual solid collected and washed with a small amount of organic solvent such as chloroform, hexane, benzene or ether, and the solid recrystallized from an appropriate solvent such as ethanol, acetonitrile or benzene.

To prepare the N-aryl-a-oxocyclopolymethylene amines (I) of this invention the above prepared haloalkanoyl anilide (V) is heated with an alkali metal cyanide in an alkanol in the presence of a catalyst, for example sodium iodide, at a temperature range from about to about 0., preferably the reflux temperature, for a period of about 1 to 20 hours affording the product a N-aryl-a-oxocyclopolymethylene amine (I) of this invention. The product may be separated and recovered by well known techniques. For instance, the inorganic material may be filtered off, the filtrate evaporated to dryness, and the residual solid recrystallized from a suitable organic solvent, such as ethanol. Preferably this reaction is conducted with potassium cyanide, in ethanol, in the presence of a catalytic amount of sodium iodide, at reflux temperatures for about 6-20 hours.

To prepare the N-aryl-a-oxo-a-iminocyclopolymethylene amines (II) of the present invention, a haloalkanoyl anilide (V) is heated with an alkali metal cyanide in an alkanol, e.g. absolute ethanol, at a temperature range of about 50 to about 100, for a period of about 6 to 20 hours. Preferably this reaction is conducted with potassium cyanide in ethanol at reflux temperatures for about eight hours. The product (II) is recovered by well known techniques. For instance, the inorganic material may be removed and the residue concentrated and then dissolved 3 in benzene. The benzene solution is then washed with water, dried over magnesium sulfate, and treated with activated carbon, such as Darco. After the benzene is removed the residue may be dissolved in ethanol, where- 4 is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to upon the solution upon scratching will afford the product produce the same effect as a smaller quantity given paren- N-aryl-u-oxocyclopolymethylene amine (I) as aprecipitate terally. In general, the compounds of this invention are which is filtered off. Thereafter the filtrate is evaporated, most desirably administered at a concentration level that and the residue dissolved in ether, the ether solution on will generally afford effective results without causing any cooling yields the N-aryl-a-oxo-a-iminopolyrnethylene harmful or deleterious side effects.

amine (II) of the present invention. In order more clearly to disclose the nature of the The new and novel N-aryl-a-oxocyclopolymethylene present invention, specific examples of the practice of the amines (I) and N-aryl-a-oxo-a-iminocyclopolymethylene invention are hereinafter given. It should be understood, amines (II) of the present invention have exhibited dehowever, that this is done solely by way of example and pressant properties. That is, they produce a calming efis intended neither to delineate the scope of the invention feet in the host. or limit the ambit of the appended claims.

In the pharmacological evaluation of the central nervous EXAMPLE 1 system activity of the compounds of this invention, the D in vivo effects are tested as follows. The compound is ad- The foiiowmg f h {nustrates the PrePamtmn of ministered orally to three mice (14 to 24 grams) at each trichloropropionamhde and 1 (za6'dlchlorophen of the following doses: 400, 127, 40 and 12.7 mg./kg. y

The animals are watched for a minimum of two hours p A during which time signs of general stimulation To 200 g. (1.23 m.) of 2,6-dichloroaniline in 500 ml. creased Spontaneous motor activity, hyperactivity on of chloroform is added a solution of 200 g. (1.60 m.) of tactile Stimulation, twitching), general depression 3-chloropropionyl chloride in 200 ml. chloroform. The decreased Spahtaheous motor activity, decreased P mixture is heated to reflux for 4 hours and let stand overtion) and autonomic activity miOSiS, y e i night. The white solid which separates is collected and i' are noted- The eompouhds of the Present invention washed with ethanol and ether. The crude material weighs 1n the above F e pioeedili'e induce depressant effect? at 276 g. The pure 2,3,6'-trichloropropionanilide is obtained 127 i0 400 milligrams P kiiogrem of host y weight by recrystallization from ethanol and has a melting point ge-)- of 140-141" c.

When the compounds of this invention are employed as Analysis' calculated f C H ChNO c described above, they may be administered alone or in 42 H, 3J9; 1 4212; N, 555 Found C combination with pharmacologically acceptable carriers, 4299.131 c1 4135. N 562. the proportion of which is determined by the solubility i and chemical nature of the compound, chosen route of step B administration and standard pharmacological practic A solution of 7.5 g. (0.03 m.) of 2',3,6-trichloropro- For example, they may be administered orally in the pionanilide and 2.9 g. (0.45 m.) of potassium cyanide form of tablets or capsules containing such excipients as are h t d t fl x in 200 1, of absolute ethanol for Starch, milk, Sugar, Certain yP of y and S0 fOTih- 8 hours. After removal of inorganic material, the solvent Th y m y e m ni l g y in the form Of is removed and the residue picked up in benzene. The troches or lozenges in which the active ingredient is mixed benzene 1 ti i fi t wa hed ith water, then dried With Sugar and Com y p and then dehydrated Silifiover anhydrous magnesium sulfate and treated with Dareiehiiy to make it Siliiahie for Pressing into a solid formco. After benzene is removed, the residue is dissolved y y be administered Orally in the form of SOhlin 10 ml. of ethanol. The solution upon scratching aftions or y y be injected parenterally. that i i fords 1.2 g. of 1-(2,6-dichlorophenyl)-2-azetidinone. m y, intravenously r subcutaneously- For p After recrystallization from the same solvent the product teral administration they may be used in the form of a h a melting point of 112-113 C, I sterile solution containing other solutes, for example, Analysis.-Calculated for CgHqClzNO (percent): C, enough saline or glucose to make the solution isotonic. 50.01 H, 3.26; C1, 32.81; N, 6.48. Found (percent): C,

The dosage of the present pharmacological agents will 5 47; H, 3.19; C] 3291; 6g vary with the form of administration and the particular compound chosen. Furthermore, it will vary with a par- EXAMPLES 244 ticular subject under treatment. Generally, treatment is Following the procedure of Example 1 but substituting initiated with small dosages substantially less than the the following starting materials for 2',3,6' trichlorooptimum dose of the compound. Thereafter, the dosage propionanilide the following products are obtained.

Example Starting material Product, step B Product, step 0 2 2, 4, 4, 6-tetrabromobutyranilide 1-(2,4,(i-tribromophenyl)-2-pyrrolidinone.. 1-(2,4,6-trlbromophonyl)-G-iminopiporldin-2- 3 5-cllloro-2,4'-difiuoro-6-sulfam0yl-valeraull-(2,4-diflu0ro-6-sulfamoylpltenyl-)Z-plperll-( f i dlfluolo-6sulfarnoylphcnyl)-7-im1n0- l1de dlnono. hexal1ydroazepln-2hne. 4 3,5-dlchloro-2,4-dllodoproplonanillde 1-(5-cl1lore-6, i-diiodopllenyl)-2-azetidlnone 1-(d-chloro-ZA-diiodophonyl)-5-imlnopyr- 5 4,G-dicl1loro-2,5-dimethylbutyranilidc l-(ti:chlore-2,5-dimethylpheny1)-2-pryrroll- 1-(h hiiiggi siimethylphenyl)45-lmiuo i- 6 4,5-dibromo-2etl1yl6-propylvaleranilid0..- 1-(4i io2-ethyl-6-propylphenyl)-2-plperi- 1-(232i?)$i i hylhpropyphenyl)-7-irninc- I I I none. l1exahydr0azepin-2-one. 7 345113115??? ethyl-5 fluoro-2-propylprop10n- 1-(gat1:551-5 fluoro-2-propylphenyl)-2-azotl- 1-(3ethy l-5-lluoro-2-propylplienyl)-5-i1n1no- 8 2, 5-dibntyHA-dliodobutyranllidc l-(2,531iliutylt-iodophonyl)-2-pyrrolldinone- 1-( iii iiigigf l ibiiophenyl)-6-iminopl 9 5-ehloro-3-methy1-2,5-dimcthoxyvalcran- 1-(ii-metllyl-2-5-dimethoxyphcnyl)-2-piperll-(g rigiiiil i -dlmethoxyphenyl) 7-imi olllde. dinone. hexahydroazepln-Q-one. 10 3-brom0- i -but0xy-6-ethyl-2-etl1oxy-prol-( i butoxy-fi-cthyl-Zethoxyphenyl)-2-azetl- 1-(4-butoxy-G-ethyl-Z-ethoxyplienyl)-5-im1noplonarnlide. dlnone. pyrrolldln-Zone. 11.-. 4,6'-d1chloro-4-methoxy-2-propoxybuiyr- 1-(ti-chloro l-methoxy-2'propoxyphenyl)-2- 1-(ti chloro4-methoxy-2-propoxyphcnyl)-6- anilide. pyrrolldrnone. iminopiperidin-2-one. 12 5,5 4lbIODJO'2',3'-dlbJt0XyV316I31ll1ld0 1-(5 -bromo-2,3-dibutoxyphenyl)-2-plperl- 1-(5-bromo-2,3-dibutoxyphenyl)-7-lminodlnone. hexahydroazepin-2-one. 13 2',3-dich1oro-4-sulfamoylproplonanlllde 1-(2-chloro4-snliamoylphenyl)-azetldin0ne..- 1-(2chloro-4-sulfarnoylphenyl)-5-lminopyr- 14 2,4-dichlorofl-methylbutyranllide 1-(2-chloro-5-n1cthylpllenyl)-pyrrolidlnone. l-g l iiiethylphenyl-G-iniinoplperldin-Zone.

This example illustrates the preparation of 1-(2,6- dichlorophenyl)-5-iminopyrr0lidin-2-one.

Following the procedure of step A of Example 1, 2',3,6'-trichloropropionanilide is prepared.

A solution of 7.5 g. (0.03 rn.) of 2',3,-6'-trichloropropionanilide and 2.9 g. (0.045 m.) of potassium cyanide are heated to reflux in 200 ml. of absolute ethanol for 8 hours. Inorganic material is removed, and the residue is concentrated, then dissolved in benzene. The benzene solution is first washed with water, then dried over anhydrous magnesium sulfate and treated with Darco. After benzene is removed, the residue is dissolved in 10 ml. of ethanol. The solution upon scratching afiords 1.2 g. of l-(2,6-dichlorophenyl)-2-azetidinone. Ethanol is removed from the above filtrate and the residue dissolved in ether. The ether solution yields 1.4 g. of 1-(2,6-dichlorophenyl)-5-iminopyrrolidin-2-one. Recrystallization from cyclohexane affords the pure compound having a melting point of 147-149 C.

Analysis.Calculated for CmHgClgNgO (percent): C, 49.40; H, 3.32; C], 29.17; N, 11.53. Found (percent): C, 49.47; H, 3.59; Cl, 28.78; N, 11.45.

The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

What is claimed is:

1. 1-(2,6-dichlorophenyl)-5-iminopyrrolidin-2-one.

References Cited UNITED STATES PATENTS 6/1942 Haddock 260-325 1/1969 Taylor 260326.5

OTHER REFERENCES ALEX MAZEL, Primary Examiner B. I. DENTZ, Assistant Examiner U.S. Cl. X.R.

' m I UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,637, 7 46 Dated January 21 19 72 Inv n (s) Peter H. L. Wei and Stanlev C. Bell It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the structural diagram at page 1, column 2, formula V, I and II shouldread as follows:

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(I) (II) Signed and sealed this 11th day of July 1972.

L (SEAL) I Attest:

EDWARD PLFLETCHFR, JR. ROBERT GOTTSCHALK Attes ting Officer Commissioner of Patents 

